Abstract Precisely characterizing HIV rebound when antiretroviral therapy (ART) is stopped can offer valuable insights into HIV reservoirs including: ? What biological quantities can predict viral rebound dynamics (timing, set-point, slope), ? How HIV populates blood cells and anatomic compartments, and ? What immune mechanisms are associated with HIV population size and activity, rebound characteristics, and viral population of circulating CD4+ T cells and tissues. A sticky clinical research dilemma is that clinical compromise can occur when ART is stopped. To overcome these dilemmas, the proposed Revealing Reservoirs during Rebound (R3) will: ? Analyze currently available clinical, virological and immunological data from 504 well-characterized participants who started ART during acute and early infection, achieved sustained viral suppression, and then interrupted this therapy under monitored studies (Early Treatment Research Project); ? Generate new virologic and immunologic data from blood samples collected from 60 participants in the Zurich Primary Infection cohort and 30 participants in the AIDS Clinical Trials Group study ?Identification of Biomarkers to Predict Time to Plasma HIV RNA Rebound and Post-Treatment Viral Control during an Intensively Monitored Antiretroviral Pause (IMAP)? (A5345) (Early Treatment Research Project); ? Evaluate 20 altruistic HIV-infected people on ART who are terminally-ill and who have voluntarily decided to stop their ART before they die, and who will provide us their blood before and after they stop ART, then their bodies after they die (Late Treatment Research Project); ? These large and diverse sets of data, which will require the development of new analytical methods to answer important questions relevant to the HIV cure agenda (Quantitative Methods Research Project). These three Research Projects will be supported by three Cores. ? The Administrative Core will ensure effective and efficient management of the program; ? The Clinical and Pathology Core will ensure appropriate collection and management of R3 specimens; ? The Quality Assurance and Data Core will ensure quality of data that are collected, generated and analyzed across the program. Altogether, the R3 will address these open questions to provide tangible metrics to guide the development of HIV cure strategies and inform the use of biomarkers to ascertain whether or not a cure effort has the intended effect without interrupting ART.